Self-boosting vaccine could give single-shot immunity

The cost: a lingering, symptomless viral infection.

Vaccines are one of the most successful public health interventions we've developed—a simple injection can lead to a life-long immunity to disease-causing agents. But not every vaccine is so successful; for a number of agents, regular booster shots are needed to prevent immunity from fading. But researchers are starting to look into a possible route around this problem: a self-boosting vaccine. The challenge will be making one that's safe and acceptable to the public.

Immunity works because some of the cells that recognize pathogens we're exposed to get set aside as "memory" cells. When the pathogen reappears, these cells are able to rapidly mobilize an assault on the invader, clearing it before it can even cause much in the way of symptoms. But some pathogens never manage to set off a full-intensity immune response, and the resulting memory gradually fades. To maintain immunity, sporadic re-exposures (either to the pathogen or another dose of vaccine) are needed. But, as with many other things, adults have a habit of forgetting these shots or putting them off.

But a paper published in PNAS earlier this week made me aware that researchers are now looking at ways to avoid the requirement for extra shots. A self-boosting vaccine would, with a single dose, give people regular re-exposure to the proteins of dangerous infectious agents possibly handling several risks with a single dose. The downside? The method would involve giving the vaccine's recipients a lifelong viral infection.

Of course, many people already have these infections. Herpes viruses and cytomegalovirus often set up shop in human cells without causing any symptoms for years. But they also sporadically come out of hiding (rather famously in the case of the herpes family) and start a brief flare up. Although the immune system can clear the active infection, it never manages to eliminate the reservoir of quiescent virus hiding out in some cells.

In many ways, this is exactly the sort of behavior that a self-boosting vaccine would need. The sporadic activity would re-expose the immune system to any proteins carried by the virus. Since these viruses have very large genomes to start with, it would be relatively simple to engineer in additional genes without interfering with its normal cycle. In fact, it should be possible to engineer in proteins from multiple viruses, with a single vaccine providing life-long exposure to a variety of threats.

That's all on the positive side. The negative sides, however, are very substantial. Cytomegalovirus doesn't normally cause symptoms in healthy people, but it tends to be active in very young babies and among those with immune defects, where it can cause serious complications. Herpes viruses cause unpleasant symptoms as well. Plus, with public acceptance of vaccines having issues at the moment, convincing people that they should voluntarily get infected with one might be a very hard sell.

Obviously, the goal will be to develop attenuated versions of the viruses that are much less likely to re-activate in a way that produces any symptoms. But it can't be so attenuated that it never reactivates, or it wouldn't accomplish the whole goal of the vaccine: re-exposure to the proteins it encodes. And, right now, we don't really have a strong grasp on precisely what leads the virus to be reactivated in the first place.

The PNAS paper that pointed me towards the idea also highlights another issue with this approach to vaccination: it could change the dynamics of the herd immunity we currently rely on for public health. The paper modeled the pathogen pertussis, which children receive vaccinations against, but adults need continued boosting. Because the pathogen is still circulating at low levels, a population contains a complicated mix of people: unvaccinated, partly immune, etc. As a result, the pathogen itself helps keep immunity high by exposing some of the unvaccinated and giving others a boost without causing any symptoms.

In their model, the researchers found that the self-boosting vaccine changed the dynamics of herd immunity. Those that were vaccinated, of course, never had to worry again. But this cut down the circulation of the pathogen in general, meaning that the unvaccinated were less likely to ever get exposed. That actually led to increased disease incidence among the unvaccinated.

In any case, we're still a long way off from developing these self-boosting vaccines. But it's a clever idea that could lead to a dramatic change in the dynamics of disease prevention.

57 Reader Comments

Huh, this is kind of scary! My primary concern is mutation. Could these viruses mutate over the course of their life within their human host? Could this lead to potential problems (i.e. the vaccine virus picking up deadly mutations and then sitting in your body like a time bomb)?

It is fascinating to read about, but I am glad we're years from implementation!

Viruses as persistent as Herpes are probably the most dangerous sort, exactly because they establish themselves permanently within the body. If this approach strengths the body's immune response in a useful manner, why can't it eliminate these sorts of viruses? What happens when this virus-based immunization mutates and we start contracting the flu every few months by self-infection?

I could see this useful in cases where you're dealing with worse alternatives, like HIV/AIDS, but I'd be concerned about the vaccine becoming infectious.

I think this is really clever, but may have too many downsides for widespread human adoption. For livestock, where lifespans are shorter and we can be assured of something approaching 100% vaccination, it might be perfect.

For humans, I'd think some kind of long-lasting time-release capsule would be an easier sell. We engineer a nanostructure tube that holds many compartments, each containing the vaccine. The outer shell is basically impervious, whereas the ends self-destruct after T years of exposure to the body. The two outermost compartments dissolve first, releasing their vaccine doses and exposing the next two compartments, etc. The advantage are (1) the vaccine gets no chance to mutate between planned exposures, (2) planned exposures are a bit more planned, (3) if a vaccine gets recalled then we can fish out the capsule and replace it.

I work in gene transfer technology, developing virus-based vectors for treatment of single gene disorders. A lot of effort is placed in disabling the vectors and optimizing the production process to minimise or nullify the generation of replication competent particles.I'd be very concerned over the relatively uncontrolled release of a replication competent, genetically modified virus into the wild. What if the newly-expressed vaccine target protein had a suppressive effect on the host immune system?

The paper describes a mathematical model of a "self boosting vaccine" and its effect on herd immunity. For such an idea to be biologically feasible, one would need to reliably manipulate the frequency and context of reactivation and the immune response it triggers such that it results in protective immunity. The knowledge to do that simply does not exist today (I have an extensive background in Immunology).

Furthermore, the two examples of long lasting viral infections mentioned, CMV and HSV, are instances where the immune system fails to clear an infection; obviously not a model where long term infection leads to protective immunity. They are also infectious agents that prove very troublesome whenever the immune system weakens (age extremes, illness, chemotherapy, etc...)

If they manage to create viruses that do not threaten the host's immune system in any way I don't see why this won't be feasible in humans. Too bad it's going to take a lot of years until they come up with something useful.

Huh, this is kind of scary! My primary concern is mutation. Could these viruses mutate over the course of their life within their human host? Could this lead to potential problems (i.e. the vaccine virus picking up deadly mutations and then sitting in your body like a time bomb)?

It is fascinating to read about, but I am glad we're years from implementation!

While I am curious about the short term ramifications, the long term should be fine. Much of our DNA is already from virii. A virus that is too deadly will die out as it kills off its host. I've read that HIV is slowly becoming less deadly(ignoring medicine) as it is beneficial to keep the host alive as long as possible.

If they plan to make something like this viable, they'd also need to produce a "kill switch". That is, a treatment that could easily kill off the remaining virus that is in the body. People would balk at a "permanent" infection. However, if it could be easily enough removed, then it would be more acceptable.

"Popular culture also its myths. Take the immune system. Please. It is not a bicep that can be made stronger with a little exercise. It is a complex network of cells and proteins.

...

There is no validity to the concept, the myth, of boosting your immune system. Metaphor time. Think of the body as a meat machine, like a car made out of steak. Mmmm. Steak. You can be properly tuned and maintained, the fluids and gas topped off, the air in the tires at the proper pressure. It will run optimally. You can’t over tune the car or fill tank past capacity. There is an optimum you can’t go beyond.

It is similar with the immune system. There are certainly habits that will have everything running suboptimally, and by altering those habits get the function close to its theoretical optimum. That is the things you learned in second grade: good diet, exercise, avoid tobacco, a good nights sleep. All the things we know we should do but, the flesh being weak, we often avoid."

"Popular culture also its myths. Take the immune system. Please. It is not a bicep that can be made stronger with a little exercise. It is a complex network of cells and proteins.

...

There is no validity to the concept, the myth, of boosting your immune system. Metaphor time. Think of the body as a meat machine, like a car made out of steak. Mmmm. Steak. You can be properly tuned and maintained, the fluids and gas topped off, the air in the tires at the proper pressure. It will run optimally. You can’t over tune the car or fill tank past capacity. There is an optimum you can’t go beyond.

It is similar with the immune system. There are certainly habits that will have everything running suboptimally, and by altering those habits get the function close to its theoretical optimum. That is the things you learned in second grade: good diet, exercise, avoid tobacco, a good nights sleep. All the things we know we should do but, the flesh being weak, we often avoid."

Except the immune system isn't a "tank", and you *can* overtune a car. Car tuners generally retard the spark, which causes leaner ignition, which gives more power... up to a point, after which it causes detonation, which can wreck your engine. For this reason, normal stock engines are generally delivered in an extremely "detuned" state to create a buffer to protect the engine. Toyota engines were known for this, and it was one reason Toyota's used to have such a reputation for reliability.

Oh, and plus the entire concept of an "autoimmune" disease puts the lie to what you are saying. An autoimmune disease is exactly what you deny exists... an overactive immune system, that is more aggressive than normal at attacking invaders, resulting in "false positives", i.e. attacking the body's own cells.

Metaphors can be a dangerous thing.

edit: It's possible you meant something similar to what I'm saying, which is that you *could* boost the immune system, but it isn't normally beneficial to do so. But I don't think a tank that can't be filled further or a knob that can't be turned up to 11 would be good metaphors. I would think a better metaphor would be a goldilocks kind of scenario, which is that there is too little, too much, and just right.

I would have thought they would mention one big worry with this approach, which is that it might cause cancer. Many, many kinds of virus infections increase cancer rates, since viruses disrupt the cell reproductive mechanism, which is delicately balanced to prevent runaway reproduction, i.e. cancer.

The thing that worries me about this is the risk of adverse reactions. There are a small minority of people who are unable to have (certain) vaccines, because they have adverse reactions to them. Normally this would be discovered when they first have the vaccine, then further treatment would be stopped. But would these self-boosting vaccines give them another reaction every time they were re-exposed?

The thing that worries me about this is the risk of adverse reactions. There are a small minority of people who are unable to have (certain) vaccines, because they have adverse reactions to them. Normally this would be discovered when they first have the vaccine, then further treatment would be stopped. But would these self-boosting vaccines give them another reaction every time they were re-exposed?

Assuming we could engineer an otherwise safe self-boosting vaccine, the first dose or two would be injected normally to sniff out adverse reactions. The target seems to be the vaccines that require adults to get boosters (tetanus, pertussis, etc.), and any adult would have history with the childhood shots.

That actually led to increased disease incidence among the unvaccinated.

This isn't necessarily an entirely bad thing, since the majority of unvaccinated individuals have chosen not to vaccinate for a range of nonsensical reasons. It would be nice to have these idiots unable to rely on the herd immunity the rest of the population currently affords them.

Since complex eukaryotes are such communal organisms anyway, with ~ 95 % of their genomes (as a commune) and ~ 10 % of their metabolites constituted by their symbiont or otherwise prokaryotes, and ~ 20 % of the eukaryote genome constituted by viral genes, this isn't much of a stretch.

It is cool that the Herpesviridae and the subfamily Cytomegalovirus, which are dsDNA viruses [ http://en.wikipedia.org/wiki/Herpesviridae ], are grouped with the giant viruses. Those viruses likely branched off of cellular life forms to adapt to a parasitic life.

It is often said that viruses know more about our biology than we do, since they do so well. And some giant viruses knows more than most, since they can hide in our cells.

That is akin to our mitochondria endosymbionts. So maybe we can use these guys as similar (non-hereditary) symbionts.

Quote:

Immunity works because some of the cells that recognize pathogens we're exposed to get set aside as "memory" cells.

From this I take it the article is primarily concentrated on the adaptive immune system of antibodies, as opposed to the innate system of less variable peptides.

It is the innate system that invertebrates use to such advantage. While vertebrates are specializing on the adaptive system.

Huh, this is kind of scary! My primary concern is mutation. Could these viruses mutate over the course of their life within their human host? Could this lead to potential problems (i.e. the vaccine virus picking up deadly mutations and then sitting in your body like a time bomb)?

It is fascinating to read about, but I am glad we're years from implementation!

Of course they will mutate, as did the germ cells that constituted you, as are your somatic germ cells as we write, and as will your own germ cells. Every human has ~ 100 mutations already as a fetus, and it proceeds from there.

But it is a legitimate concern, since the other utilized genome is put under sieving and selection. For example, we choose (or not) the gut bacteria by sieving and ultimately by selection to be advantageous.

Now the selection will be done by the people wielding the needles. Not a very fast way, in the sense of sieving.

In the global sense it would be better if these helpful viruses were naturally inoculating, spreading like other viruses. Then they go rogue, they would be selected against. Instead, we have to rely on the vaccine providers to keep up with changes, as they do already today.

Viruses as persistent as Herpes are probably the most dangerous sort, exactly because they establish themselves permanently within the body.

The viruses that establish themselves most permanently are retroviruses. They can get stuck integrated into the genome, and when it happens in germ cells they can become fixated in the population.

As such, retroviruses are more a resource than a risk. Many mammals, as the sheep and the primates, have used viral adaptive immune system regulating genes to do exactly that. It is what allows some mammals like us to implant the fetus more robustly and nutritiously beneficial closer to the uterus surface.

As for Herpesviridae, this vaccine type points to how useful that type of virus can be.

Car tuners generally retard the spark, which causes leaner ignition, which gives more power... up to a point, after which it causes detonation, which can wreck your engine.

OT, but an internal combustion engines are often _based_ on detonations, they are a part of the engine cycle. I think you are talking about what space companies calls RUD, Rapid Unscheduled Disassembly.

And before fuel injection technology with its concomitant spark delivery, the spark could happen anytime. Even to the point that it retarded the engine cycle by mistiming.

What you could be referring to is that there is an optimum ignition time, but out of bounds timing can unduly wear the engine. And with added compression machinery all bets are off - you can RUD an engine with a regular ignition or more likely an irregular stress cycle.

There's an even better way than one single larger shot to boosting your immune system. I know from personal experience that working or volunteering in the back of a thrift store for 4 years certainly ought to do it. I haven't been sick with ANYTHING since 2007.

Car tuners generally retard the spark, which causes leaner ignition, which gives more power... up to a point, after which it causes detonation, which can wreck your engine.

OT, but an internal combustion engines are often _based_ on detonations, they are a part of the engine cycle. I think you are talking about what space companies calls RUD, Rapid Unscheduled Disassembly.

And before fuel injection technology with its concomitant spark delivery, the spark could happen anytime. Even to the point that it retarded the engine cycle by mistiming.

What you could be referring to is that there is an optimum ignition time, but out of bounds timing can unduly wear the engine. And with added compression machinery all bets are off - you can RUD an engine with a regular ignition or more likely an irregular stress cycle.

Detonation is a technical term used by people who work with internal combustion engines. It is better known as "Knock" and can lead to mild on up to explosive RUD. Premature ignition is a related problem that will disassemble the piston assembly and/or cylinder heads & walls under the right conditions.

Huh, this is kind of scary! My primary concern is mutation. Could these viruses mutate over the course of their life within their human host? Could this lead to potential problems (i.e. the vaccine virus picking up deadly mutations and then sitting in your body like a time bomb)?

It is fascinating to read about, but I am glad we're years from implementation!

While I am curious about the short term ramifications, the long term should be fine. Much of our DNA is already from virii. A virus that is too deadly will die out as it kills off its host. I've read that HIV is slowly becoming less deadly(ignoring medicine) as it is beneficial to keep the host alive as long as possible.

Sorry, I am not trying to be rude or anything...but HIV is rather parasitic and won't keep the host alive as long as possible out of mercy. It just means a slower, much more painful death.

No thanks, I'll just setup a calendar reminder in x years to get the booster shots for whatever vaccines I need. I've already setup a reminder to get the shingles vaccine if I hit 60, having seen how unpleasant it is.

Detonation is a technical term used by people who work with internal combustion engines. It is better known as "Knock" and can lead to mild on up to explosive RUD. Premature ignition is a related problem that will disassemble the piston assembly and/or cylinder heads & walls under the right conditions.

Ah, thank you! Now I feel foolish as my translation made the comment so out there, and I should have realized I was off basis. (Funny thing is that I drove a car in US for two years, but since I never had any problems with detonations...) Another technical term that is "out there" then, akin to RUD.

AWTY and I ended up describing nearly the same phenomena. And you are entirely correct that I messed up the difference between detonation and knock. I wonder if my car will ever forgive me?

Several people have posted concerned about the virus mutating and becoming capable of infecting others and using the added disease genes to become a kind of super flu. The super virus part would be very unlikely because something like this would use specific pieces of proteins to immunize with, not a whole functioning protein. It should also be relatively easy to create a virus that is very unlikely to spread other than by blood exposure by eliminating whole parts of the virus so that point mutations are not enough to make the virus functional again. This has been done before, with the genes needed for replication expressed by specifically engineered cell lines, so that the virus is only able to multiply in those cells and not normal human cells. For gene therapy this is trickier since you want the virus to then target a specific cell type and in high enough numbers to fix the problem without causing other problems, like rare integration at sites causing cancer or the immune system targeting every cell with the therapeutic virus.

The biggest problem as I see it the chronic reactivating infection. How exactly do you make a virus that you can gut of everything dangerous yet still be able to persist and reactivate? Herpes viruses are able to persist at a low level without causing disease because they have very large (for a virus) and complicated genomes. Still, they do cause problems, particularly for the immunosuppressed. If you're going to give someone a chronic reactivating virus, what cells is it going to reside in while latent? I can't see how you will ever prove to regulators satisfaction that those cells wont become eventual targets of autoimmunity. On top of that, the cells would have to do more than just express the vaccine proteins, there would have to be some sort of inflammatory trigger as well, otherwise you might end up tolerizing people instead of immunizing.

Overall, I think the problems with this method would be make it very difficult to ever get approved for use in people.

While I am curious about the short term ramifications, the long term should be fine. Much of our DNA is already from virii. A virus that is too deadly will die out as it kills off its host. I've read that HIV is slowly becoming less deadly(ignoring medicine) as it is beneficial to keep the host alive as long as possible.

Sorry, I am not trying to be rude or anything...but HIV is rather parasitic and won't keep the host alive as long as possible out of mercy. It just means a slower, much more painful death.

I seem to remember that HIV mutates so fast that the genome isn't as much as a near point like volume of a fitness space, but a swarm populating it. When humans gets infected, it could possibly be an initial allele spread already.

In any case, HIV mutates fast in many directions (many alleles in parallel) as evidenced by both its ability to avoid the immune system and its developing of resistance against individual antivirals over time. It is like cancer that way, only faster. And the latter pathway is why HIV is hit with a cocktail of multiple antivirals at any given time.

My hunch is that it evolves and infects too rapidly for the subsequent death of the individual to matter much.

Simian immunodeficiency viruses, SIVs, are in most, but not all, cases much less deadly for their hosts.

The mechanism by which that happen is, I think, believed to be the retrovirus itself. Pieces of it get stuck in the cell's genome at times, and if active genes the viral proteins can be recognized as "self" under infection.

When the gene transfer happens in germ cells it becomes horizontal gene transfer as regards evolution, the genes becomes stuck as a selectable trait in the population. A beneficial trait would rapidly overtake a population since an unchecked SIV is so deadly.

Huh, this is kind of scary! My primary concern is mutation. Could these viruses mutate over the course of their life within their human host? Could this lead to potential problems (i.e. the vaccine virus picking up deadly mutations and then sitting in your body like a time bomb)?

It is fascinating to read about, but I am glad we're years from implementation!

While I am curious about the short term ramifications, the long term should be fine. Much of our DNA is already from virii. A virus that is too deadly will die out as it kills off its host. I've read that HIV is slowly becoming less deadly(ignoring medicine) as it is beneficial to keep the host alive as long as possible.

I hate to be that guy, but because the name of the site is in Latin...

The English plural for virus should be viruses. Anything else is a hyper-correction. In classical Latin, "virus" is a mass noun and there is no attested plural form for it. For "virus" to be pluralized in English, it should take on a standard plural form.

The closest word I'm aware of to virii is viri which would be the plural nominative for 'men". It's kind of nuts. "-us" plurals are hard in English.

On another note: why would a virus push for selectivity beyond reproduction and transmission? If you manage to pass on HIV to someone else, it doesn't matter how quickly you die...

In their model, the researchers found that the self-boosting vaccine changed the dynamics of herd immunity. Those that were vaccinated, of course, never had to worry again. But this cut down the circulation of the pathogen in general, meaning that the unvaccinated were less likely to ever get exposed. That actually led to increased disease incidence among the unvaccinated.

Actually this was the most interesting part for me. Typical herd characteristics include a significant population of symptom-free carriers who maintain immune memory by passing the pathogen among themselves, but also represent a serious infection risk for those without any form of immunity. Eliminating such carrier states is an important goal of most disease eradication programs. Also, would the modified booster virus lack any transmissibility of its own? As an example, passive faeco-oral vaccination is a recognised element of the operation of the Sabin vaccine. Herpes viruses are, after all, pretty easy to pass around.

All-in-all, I find this idea quite intriguing. How many books, movies and shows have been made about the Zombie Apocalypse? It's clearly something the public wants.... But seriously, while a lot of work would need to be done to ensure its safety, we already use a lot of attentuated-virus vaccines that are acceptably safe (oral polio vaccine has a 1 in 2.7million chance of causing paralysis, but it's worth the risk).

No thanks, I'll just setup a calendar reminder in x years to get the booster shots for whatever vaccines I need. I've already setup a reminder to get the shingles vaccine if I hit 60, having seen how unpleasant it is.

I would suggest 50 years of age. I got shingles TWICE, once at 55 and then again at 58. No damn fun either time. I believe they've modified that suggestion now to 50. I went to a drug store and got the shot by lying about my age at 59, never thought I'd have to do that after 21.

BTW my doctor said I shouldn't have gotten it twice but he diagnosed it both times. Steroids seem to be the only treatment for them which generate their own nasty "symptoms". I wasn't going to wait to have it three times. The kids of the most recent generations hopefully won't have to suffer from shingles later in life since they've finally got a chicken pox vaccine.

Huh, this is kind of scary! My primary concern is mutation. Could these viruses mutate over the course of their life within their human host? Could this lead to potential problems (i.e. the vaccine virus picking up deadly mutations and then sitting in your body like a time bomb)?

It is fascinating to read about, but I am glad we're years from implementation!

Sure they could... but are you asking what the chances are? If the virus is truly quiescent and has stably integrated itself into your DNA? Probably not very likely. Your body is already a ticking time bomb of potentially picking up mutations (cancer),

Also our DNA is probably already littered with the remnants of inherited viral integrations. I wouldn't be surprised if some of that isn't already helping the immune system, for example by producing trace amounts of viral proteins to serve as antigens. So really, it isn't a question of if we should start doing this, but whether if we should be taking advantage of it.

Several people have posted concerned about the virus mutating and becoming capable of infecting others and using the added disease genes to become a kind of super flu. The super virus part would be very unlikely because something like this would use specific pieces of proteins to immunize with, not a whole functioning protein. It should also be relatively easy to create a virus that is very unlikely to spread other than by blood exposure by eliminating whole parts of the virus so that point mutations are not enough to make the virus functional again. This has been done before, with the genes needed for replication expressed by specifically engineered cell lines, so that the virus is only able to multiply in those cells and not normal human cells. For gene therapy this is trickier since you want the virus to then target a specific cell type and in high enough numbers to fix the problem without causing other problems, like rare integration at sites causing cancer or the immune system targeting every cell with the therapeutic virus.

The biggest problem as I see it the chronic reactivating infection. How exactly do you make a virus that you can gut of everything dangerous yet still be able to persist and reactivate? Herpes viruses are able to persist at a low level without causing disease because they have very large (for a virus) and complicated genomes. Still, they do cause problems, particularly for the immunosuppressed. If you're going to give someone a chronic reactivating virus, what cells is it going to reside in while latent? I can't see how you will ever prove to regulators satisfaction that those cells wont become eventual targets of autoimmunity. On top of that, the cells would have to do more than just express the vaccine proteins, there would have to be some sort of inflammatory trigger as well, otherwise you might end up tolerizing people instead of immunizing.

Overall, I think the problems with this method would be make it very difficult to ever get approved for use in people.

Well there's what we think, and there's what nature thinks, and I'd be willing to bet money that nature has already employed this mechanism. That even as you speak, latent viral infections in your DNA are already helping you out.